Pharmaceutical compositions containing an effervescent acid-base couple

ABSTRACT

A pharmaceutical formulation in the form of a fast dissolving tablet comprising an active ingredient, sodium glycine carbonate and an acid capable of reacting rapidly with sodium glycine carbonate to release carbon dioxide.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

[0001] This invention relates to orally administered, solid,fast-soluble pharmaceutical compositions containing an effervescentacid-base couple, suitable for dissolving in water or an aqueoussolution and for sucking.

[0002] The effervescent tablets occupy an important position amongdosage forms, being the form of choice not only for adults but also forchildren. Many drugs, and in particular analgesics, vitamins andantibiotics were designed in this kind of formulations.

[0003] The effervescent tablets, when added to cold water, generate agas which causes effervescence and produces a clear sparkling solution.The gas which gives the effervescence is always carbon dioxide whichderives from the reaction between an acid and a base like carbonate orbicarbonate. The effervescent tablet consists of at least threecomponents:

[0004] the active ingredient;

[0005] an acid;

[0006] an alkali compound (basic ingredient) constituted by a carbonateor a bicarbonate.

[0007] The acid and the alkali are the essential components whichprovide the effervescence and the disintegration of the tablet when iscontacted with water. As acidic component the citric acid both in thehydrated and anhydrous forms is more often used, but other edible acidslike tartaric, fumaric, adipic, malic acid can be used as well. Thecarbonate, which represents the source of carbon dioxide which generatesthe effervescence, generally is a water-soluble alkaline carbonate. Thechoice of the carbonate is very important since, besides provoking theeffervescence, it can influence the stability of the tablet. Sodiumbicarbonate is one of the most used carbonate because it is very solubleand of low cost. Alternatively, modified sodium bicarbonate can be used,obtained by heating common sodium bicarbonate in order to convert thesurface of its particles to sodium carbonate so increasing itsstability.

[0008] Other physiologically acceptable alkaline or alkaline earth metalcarbonates may be used, such as potassium or calcium (bi)carbonate,sodium carbonate, or sodium glycine carbonate.

[0009] Compositions of effervescent tablets may also include a lubricantwhich has to be necessarily selected from the totally water solublecompounds forming a clear solution. Examples of this kind of lubricantsare sodium. benzoate, sodium acetate, fumaric acid, polyethylenglycols(PEG) higher than 4000, alanine and glycine.

[0010] Conventional excipients such as diluents, ligands, bufferings,sweeteners, flavourings, colorings, solubilizers, disintegrants, wettingagents and other excipients of common use may be added to theformulation. Effervescent tablets are convenient, attractive, easy touse premeasured dosage forms. These advantages, however, are balanced bysome technological problems, the two most important of which arehygroscopicity and lubrication.

[0011] The instability of effervescent tablets, their tendency to absorbmoisture and lose reactivity are generally known. Due to thisinstability in the presence of water, conventional wet granulation andthe subsequent granulate compression are very hardly applicable.

[0012] Sometimes the granulation has been carried out using very lowamounts of water, for example through the fusion of the citric acidmonohydrate, which upon heating releases part of the water ofcrystallisation which acts as the granulating fluid. Then the granulatehas to be processed in conditions of severely controlled relativehumidity, normally lower than 20%.

[0013] Alternatively, techniques of anhydrous granulation, in theabsence of aqueous phases, have been applied using volatile organicsolvents like ethanol. However such techniques require specialmanufacturing environments with strictly controlled relative humidityconditions (normally lower than 20%) and with explosion proof equipment.

[0014] Another technique, which is more time-consuming and morelaborious, is represented by the separated wet granulation of acidic andalkali granules, which are subsequently mixed and compressed to give thefinal pharmaceutical composition.

[0015] The direct compression of the simple physical blend of thecomponents of the formulation represented an attempt to obviate theabove technological difficulties. However such an operation has beencarried out in controlled thermo-hygrometric conditions, for example attemperatures lower than 20-25° C. and with relative humidity lower than30%, using tabletting machines with tapered dies and punches faced withchromium alloys.

[0016] Because of the operating and stability problems, this type ofmanufacturing method cannot be easily applied to the preparation ofeffervescent tablets of particular active ingredients which cannot bewet granulated or which contain a residual percentage of water ofcrystallisation which. is hardly eliminated. Typical examples of thiskind of medicaments are drug cyclodextrin complexes, hydrated activeingredients and their salts, which may present stability problems in thepresence of water. Similar problems are encountered when the compositioncontains excipients having hydration water or residual-hardly eliminablemoisture. Typical examples of this kind of excipients are cyclodextrins.

[0017] The other important technological problem affecting themanufacture of effervescent tablets is lubrication, as the lubricantmust not only have lipophilic properties for good lubrication, but alsohigh water solubility, to give adequate disintegration and producequickly a clear solution. Most substances used as lubricants, such asmagnesium stearate, are effective, but are water insoluble. Theresulting solution after disintegration is cloudy and often has a soapytaste. Ideally, non toxic lubricants with high water solubility andacceptable taste are required. Moreover, the effervescent base isinherently difficult to lubricate, partly due to the nature of the rawmaterials used and partly due to the rapid tablet disintegration usuallyrequired which limits the use of high percentage of lubricants.

BRIEF SUMMARY OF THE INVENTION

[0018] Now it has been found, and this is an object of the presentinvention, that effervescent tablets can be prepared through simpletechniques which have direct-industrial application and which are basedon the use of a particular effervescent blend of acids and sodiumglycine carbonate, provided in a sufficient amount to rapidly disperseand assist dissolution of the components of the formulation.

[0019] In particular, according to a second aspect of the invention, itwas found that the use of a blend of certain acids with sodium glycinecarbonate allows to prepare effervescent tablets by direct compressionin normal thermohygrometric conditions and with standard tablettingequipment.

[0020] It has been even more surprisingly found that this technologyapplies also to active ingredients and/or excipients which cannot bewet-granulated or which contain a residual percentage of hardlyeliminable crystallisation water.

[0021] According to a further aspect of the invention, it was found thatthe use of certain acids/sodium glycine carbonate blend is particularlyadvantageous in the preparation of effervescent tablets which contain acyclodextrin as the component of an inclusion complex or as anexcipient, despite of the fact that cyclodextrins have hydration waterand tend to absorb moisture very easily.

DESCRIPTION OF RELATED ART

[0022] The characteristics of excipients which can be used in thepreparation of effervescent tablets, have been described in Aiache J M,Pharm Acta Helv 49 (5/6), 169-178, 1974 and in Boymond C, Labo-PharmaProbl Tech 25(271), 987-995, 1977.

[0023] Anyway, Faguet J P et al. in Labo-Pharma Probl Tech 26(274),207-210, 1978, after evaluating the effects of moisture on the stabilityof acids, carbonates and bicarbonates, conclude that when sodium glycinecarbonate, which is per se moisture—sensitive, is blended with an acid,specifically citric acid, the resulting carbonate is verymoisture—unstable, much more than sodium glycine carbonate alone.

[0024] In some patents, sodium glycine carbonate is simply mentioned,among various different excipients, as a possible component ofeffervescent combinations which can be used in chewable tablets (EP396335), in formulations which form a suspension when contacted withwater (EP 528846), in compositions constituted by separated acidic andalkali granules which can also comprise a moisture scavenger (ZA9307745), in oral, cold-water soluble formulations of JS-cyclodextrincomplexes with non steroidal anti inflammatory drugs like ibuprofen,naproxen or ketoprofen (WO 9504528).

[0025] However, none of the above documents teaches the preparation ofeffervescent tablets using sodium-glycine carbonate as the basiccomponent, nor suggests the possible advantages thereof.

[0026] The use of sodium glycine carbonate in effervescent formulationsis described in patent applications and scientific literature regardingformulations containing hydrated amoxycillin (PCT WO 9115197),isosorbide-5-mononitrate (DE 4416769) and enzymes (FR 2305194). Theacidic component in these formulations is constituted of citric,tartaric, malic or adipic acid and the manufacturing process foreseessteps of slugging, milling slugs, blending and compressing or the use ofanhydrous excipients or, also, an external lubrication of the machine isperformed.

[0027] Amela J. et al in the paper “Drug Dev Ind Pharm 22(5), 407-16,1996” make the analysis of various components which can be used in thepreparation of effervescent tablets and they conclude that sodiumglycine carbonate is one of the carbonates which do not have favourablecompressing characteristics.

[0028] The formulations of the invention essentially comprise:

[0029] an active ingredient;

[0030] sodium glycine carbonate;

[0031] an acid capable to react rapidly with sodium glycine carbonate torelease carbon dioxide.

[0032] One of the preferred acids is fumaric acid which may be presentin the form of salt such as mono sodium or potassium fumarate. Certainkinds of formulation take advantage by the lubricant properties offumaric acid allowing to limit the quantity of lubricant.

[0033] Another preferred acid is maleic acid eventually present as asalt.

[0034] The choice of the acid is made according to the characteristicsof the active ingredient. In some cases mixtures of acids and/or saltsare particularly suitable to modulate either the strength of the acid orthe lubricant properties.

[0035] The use of fumaric acid in effervescent formulations is describedin several documents which refer to various formulations, but never incombination with sodium glycine carbonate.

[0036] EP 443381, FR 2715849, WO 9300886, WO 9107174, WO 9104757 areexamples of patent literature which mention fumaric acid among otheracids which are commonly used in the effervescent pharmaceutical formssuch as U.S. Pat. Nos. 4,153,678, 4,812,303 and 4,704,269, referred toformulations of particular active ingredients. In other documents (amongwhich for example GB 1178294, Roscheisen G. and Schmidt P C Eur J.Pharm. Biopharm 41(5), 302-308, 1995), fumaric acid is considered as alubricant.

[0037] Maleic acid has been also described as an acidic component ofeffervescent couples but never in combination with sodium glycinecarbonate.

DETAILED DESCRIPTION OF THE INVENTION

[0038] In a particular embodiment of the invention the active ingredientof the formulation contains residual percentage of moisture or ofcrystallization water hardly eliminable. Examples of this kind of activeingredients are complexes of drugs such as the piroxicam-β-cyclodextrincomplex, levodopa methyl ester and carbidopa hydrate.

[0039] The piroxicam-β-cyclodextrin complex has been described in EP153998, wherein also an effervescent tablet formulation is exemplified.In this case citric acid-sodium glycine carbonate represented theeffervescent blend. However, tablets corresponding to the formulationexemplified in EP 153998, have unfavourable characteristics like theopacity of the produced solution, high dimension and weight and lowflowability of the pondered blend to be compressed. Moreover, thepresence of saccharose as diluent, and of sweetening agents, compromisesthe stability of the same formulation, as it has been afterwardsascertained.

[0040] The formulation may comprise other excipients like:

[0041] a lubricant selected from PEG higher than 4000 and preferably PEG6000 sodium benzoate, sodium and potassium fumarate, leucine, alanine;

[0042] a sweetening agent selected from aspartame, saccharin, cyclamate,sugars, preferably aspartame;

[0043] a diluent selected from lactose, mannitol, sorbitol or mixturesthereof and preferably spray-dried (SD) lactose and optionallyaromatizing agents, ligands, preservatives or others.

[0044] As a diluent SD lactose is particularly preferred in that itfacilitates the blend flowability so improving compressibility andmachinability of the formulation.

[0045] The particular effervescent blend of the invention, together withthe above-mentioned additives, allows highly soluble, stable andsmall-sized effervescent tablets to be prepared by direct compressingthe component mixture which can be worked at the standardthermo-hygrometric conditions of normal pharmaceutical productionfacilities, using standard to compressing machines with normal punchesand dies. Also the subsequent processing, storage and packaging of thetablets can be performed at normal temperature and moisture conditions.

[0046] The effervescent compositions of the invention solubilize oncontact with water and produce a clear solution for oral administration.Solutions are favoured over suspensions for oral administration, sincedrugs in solution are more rapidly absorbed. Solutions are also oftenmore acceptable to patients, in terms of palatability. Nevertheless insome cases the active ingredient does not dissolve and the compositiondoes not result in a clear solution, but a suspension. For this kind ofactive ingredient the possibility to prepare a tablet by directcompression and obtain a rapid disintegration anyway represents aremarkable formulation improvement.

[0047] Other advantages of the composition are the low content of sodiumions, due to the employ of sodium glycine carbonate, with respect toother sodium carbonates and the less fizzy effervescence, more pleasantto the patient.

[0048] Moreover the composition of the invention, because of its smallsize, light effervescence and rapid disintegration, can also be preparedas fast dissolving or sucking in the mouth. In fact, as introduced inthe mouth, when in contact with saliva, the tablet disintegrates andrapidly forms a solution or an aqueous dispersion easily swallowable.

[0049] The following examples further illustrate the invention.

EXAMPLE 1

[0050] Composition of an effervescent tablet having a piroxicam contentof 20 mg. Piroxicam-β-cyclodextrzn complex (1:2,5) 191.2 mg Sodiumglycine carbonate 260.0 mg Fumaric acid 180.0 mg PEG 6000 20.0 mgLactose spray-dried (SD) 208.8 mg Lemon flavour 25.0 mg Aspartame 15.0mg

[0051] Piroxicam-β-cyclodextrin, lactose SD, sodium glycine carbonate,lemon flavour, aspartame and PEG 6000 are sieved and pre-mixed. Fumaricacid is added and the components are mixed until an homogeneous blend isobtained. Then the blend is compressed in a standard rotary tablettingmachine equipped with round chromium plated punches. The process iscarried out at room temperature and with a relative humidity not higherthan 55-60%. The dimensions of the produced tablets are about 13 mmdiameter, 5 mm thickness and the weight is about 900 mg.

EXAMPLE 2

[0052] Active ingredient solution test

[0053] The analysis of the tablets prepared according to the example 1was carried out in order to determine the percentage of the dissolvedactive ingredient at the end of the effervescence. The maximumdissolution time with effervescence is 1.5 min. The experimentalconditions simulated the intake of the effervescent tablets by thepatient.

[0054] The effervescent tablet was dissolved in three kinds of water. Atthe end of the effervescence (1.5 min) the amount ofpiroxicam-β-cyclodextrin was determined in the solution. The dataobtained, which are reported in table 1, demonstrate that the activeingredient concentration in the solution is always higher than 70% ofthe nominal content per tablet. TABLE 1 Dissolution ofpiroxicam-β-cyclodextrin in 50 ml water Kind of water % activeingredient dissolved demineralized water 72.4 drinking water 85.6natural no-gassed water 77.0

EXAMPLE 3

[0055] Dissolution rate of effervescent tablets containing thepiroxicam-β-cyclodextrin complex in comparison with standard tablets.The dissolution rate of effervescent tablets prepared in Example 1 wascompared with that of standard piroxicam-β-cyclodextrin tablets usingUSP Apparatus 2 (paddles) in distilled water at a temperature of 37° C.Dissolution time Dissolved piroxicam (minutes) (%) 20 mg standardtablets 5 65% 10 100% 20 mg effervescent tablets 5 100%

EXAMPLE 4

[0056] The oral absorption profile of piroxicam released fromeffervescent tablets of piroxicam-β-cyclodextrin complex (B-CD) preparedaccording to the present invention was compared to that of piroxicam-βCDcommercially available standard tablets. The test was carried out aftersingle oral dose administration of the two formulations, equivalent to20 mg piroxicam, in sixteen healthy volunteers according to a randomizedtwo—way crossover design.

[0057] The results, reported in table 2, confirmed the behaviour of thetwo compositions in the dissolution test showing a more rapid absorptionof the active ingredient after administration of the effervescentformulation of the invention. Compared to the standard formulation, theeffervescent tablet gives remarkably higher plasma concentrations (Cp of1.93 μg/ml vs 0.77 μg/ml, respectively) 15 min after the administration,as well as a higher drug exposure during the first hour after theadministration, as it is shown by the AUC data (AUC=Area Under theCurve, i.e. the area under the plasma concentration vs time curve)collected after 1 hour. TABLE 2 Main pharmacokinetic parameters(geometric means standard deviation), statistical comparison andstandard 90% confidential intervals (90% CI). Piroxicam-β-CDPiroxicam-β-CD effervescent Pharmacokinetic tablets tablets 90% CIparameters (n = 16) (n = 16) p* Cp 15 min 0.77 (0.310-1.90) 1.93(1.33-2.80) 160%- 389% 0.003 (μg/mL) Cp 30 min 2.01 (1.47-2.73) 2.26(1.64-3.10) 100%- 127% 0.106 (μg/mL) Cp 45 min 2.15 (1.76-2.62) 2.22(1.66-2.97) 94%-114% (μg/mL) 0.570 Cp 1 h 2.08 (1.75-2.46) 2.09(1.58-2.77) 93%-109% (μg/mL) 0.845 Cmax 2.23 (1.83-2.72) 2.35(1.74-3.16) 96%-116% (μg/mL) 0.330 AUC 1 h 1.55 (1.19-2.01) 1.88(1.40-2.53) 107%- 138% 0.018 (μg · h/mL)

EXAMPLE 5

[0058] The stability of the effervescent blend and tablets preparedaccording to the example 1 was tested at 25° C. and at differentrelative humidity conditions.

[0059] Both the effervescent blend and tablets stored at a relativehumidity of 11%, 33%, 52% and 75% showed an increase in weight at thebeginning of the study, and afterwards a slight weight decrease (seetables 3 and 4).

[0060] This behavior is due to two correlated phenomena: the moistureabsorption and subsequent loss of carbon dioxide.

[0061] The moisture absorption prevails during the first days withrespect to the carbon dioxide release.

[0062] The loss of carbon dioxide however was so low that theeffervescence characteristics of the tablets were not influenced. TABLE3: Blend % weight variation at room temperature (about 25° C.) atdifferent relative humidity (R.H.) conditions. Days R.H. 1 2 3 4 7 9 1111% 0.06 0.09 0.11 0.09 0.08 0.07 0.07 33% 0.22 0.24 0.23 0.22 0.21 0.200.20 52% 0.30 0.30 0.29 0.29 0:27 0.27 0.27 75% 0.42 0.42 0.41 0.40 0.350.33 0.34

[0063] TABLE 4 Tablets % weight variation at room temperature (about 25°C.) at different relative humidity (R.H.) conditions. Days R.H. 1 2 3 47 9 11 11% 0.05 0.10 0.14 0.10 0.08 0.07 0.07 33% 0.19 0.20 0.20 0.180.17 0.16 0.16 52% 0.26 0.25 0.24 0.23 0.21 0.21 0.20 75% 0.17 0.15 0.130.12 0.08 0.07 0.07

[0064] The effervescent blend and tablets according, to the presentinvention absorb a very low quantity of water (3,5% for the blend and3,0% for the tablets) even in very unfavourable storage conditions, forexample 11 days at 75% relative humidity.

[0065] In these particularly unfavourable conditions, the chemical,technological and effervescence characteristics of the tablets are notsubstantially modified, as it results from tables 5 and 6. TABLE 5Moisture per cent values and blend purity after 11 day storage atdifferent relative humidity conditions Initial 11 day values Test value11% R.H. 33% R.H. 52% R.H. 75% R.H. 1) Moisture 2.4 3.6 4.1 4.5 5.9  (%) 2) Purity <0.005 <0.005 <0.005 <0.005 <0.005

[0066] TABLE 6 Chemical and technological characteristics of the tabletsafter 11 day storage at different- relative humidity conditions Initial11 day values Test value 11% R.H. 33% R.H. 52% R.H. 75% R.H.Effervescence con- conforms conforms conforms conforms characteristicsforms (disint. ≦ 5 min) 1) Moisture 2.5 3.3 3.9 4.4 5.5   (%) 2) Purity<0.005 <0.005 <0.005 <0.005 <0.005

[0067] With analogous process as described in Example 1 the followingtablet formulations have been prepared:

EXAMPLE 6

[0068] Ambroxol hydrochloride a) Ambroxol hydrochloride 30 mg Lactose SD800 mg Sodium Glycine Carbonate 400 mg Fumaric Acid 260 mg PEG 6000 40mg Aspartame 30 mg

[0069] The mixture is compressed directly into tablets with a diameterof 17 mm and a thickness of 5.5 mm. b) Ambroxol hydrochloride 60 mgLactose SD 600 mg Sodium Glycine Carbonate 400 mg Maleic Acid 250 mg PEG6000 40 mg Aspartame 30 mg

[0070] The mixture is compressed directly into tablets with a diameterof 17 mm and a thickness of 5.0 mm.

EXAMPLE 7

[0071] Paracetamol Paracetamol (acetaminophen) 500 mg Sodium GlycineCarbonate 260 mg Fumaric Acid 180 mg PEG 6000 10 mg

[0072] The mixture is compressed directly into tablets with a diameterof 13 mm and a thickness of 5.1 mm.

EXAMPLE 8

[0073] Paracetamol/Domperidone Maleate combination Paracetamol(acetaminophen) 500 mg Domperidone maleate 10 mg Sodium GlycineCarbonate 400 mg Fumaric Acid 300 mg PEG 6000 10 mg Aspartame 20 mg

[0074] The mixture is compressed directly into tablets with a diameterof 15 mm and a thickness of 5.7 mm.

EXAMPLE 9

[0075] Nimesulide a) Nimesulide 50 mg Lactose SD 500 mg Sodium GlycineCarbonate 800 mg Fumaric Acid 180 mg PEG 6000 40 mg

[0076] The mixture is compressed directly into tablets with a diameterof 17 mm and a thickness of 5.2 mm. b) Nimesulide 50 mg Betacyclodextrin300 mg Lactose SD 50 mg Sodium Glycine Carbonate 300 mg Fumaric Acid 180mg PEG 6000 20 mg

[0077] The mixture is compressed directly into tablets with a diameterof 13 mm and a thickness of 4.98 mm.

EXAMPLE 10

[0078] Ibuprofen Ibuprofen 200 mg Lactose SD 610 mg Sodium GlycineCarbonate 600 mg Fumaric Acid 360 mg PEG 6000 30 mg

[0079] The mixture is compressed directly into tablets with a diameterof 20 mm and a thickness of 5.2 mm.

EXAMPLE 11

[0080] Morniflumate Morniflumate 175 mg Lactose SD 300 mg Sodium GlycineCarbonate 650 mg Fumaric Acid 800 mg PEG 6000 50 mg

[0081] The mixture is compressed directly into tablets with a diameterof 20 mm and a thickness of 5.0 mm.

EXAMPLE 12

[0082] Levodopa methyl ester (LDME) LDME 314 mg Lactose SD 146 mg SodiumGlycine Carbonate 260 mg Fumaric Acid 180 mg

[0083] The mixture is compressed directly into tablets with a diameterof 13 mm and a thickness of 5.0 mm.

EXAMPLE 13

[0084] Carbidopa monohydrate Carbidopa monohydrate 27 mg Lactose SD 433mg Sodium Glycine Carbonate 260 mg Fumaric Acid 180 mg

[0085] The mixture is compressed directly into tablets with a diameterof 13 mm and a thickness of 5.0 mm.

EXAMPLE 14

[0086] LDME/Carbidopa monohydrate combination LDME 314 mg Carbidopamonohydrate 27 mg Lactose SD 539 mg Sodium Glycine Carbonate 520 mgFumaric Acid 360 mg PEG 6000 40 mg

[0087] The mixture is compressed directly into tablets with a diameterof 17 mm and a thickness of 5.0 mm.

EXAMPLES 15, 16 AND 17

[0088] Dissolution rates of the formulations of the examples 6, 7 and 14determined with the USP Apparatus 2 (paddles).

EXAMPLE 15

[0089] Ambroxol Hydrochloride

[0090] Conditions: medium=HCl 0.1 N; volume=750 ml;

[0091] speed=50 rpm (rounds per minute); temperature=37° C. time: 5 min

[0092] % of dissolved drug: 98%

EXAMPLE 16

[0093] Paracetamol

[0094] Conditions: medium=distilled water; volume=900 ml; speed=50 rpm;

[0095] temperature=37° C.

[0096] Time: 5 min

[0097] % of dissolved drug: 90.9%

EXAMPLE 17

[0098] LDME/Carbidopa monohydrate combination

[0099] Conditions: medium=HCl 0.1 N; volume=750 ml; speed=50 rpm;

[0100] temperature=37° C.

[0101] Time: 5 min

[0102] % of dissolved Carbidopa: 94%

[0103] % of dissolved LDME: 99%

EXAMPLE 18

[0104] (a) Apomorphine tablets (5 mg) Amormorphine hydrochoride 5.00 mgMannitol (Pearlitol ® DC 200) 135.50 mg Fumaric acid 20.00 mg SodiumGlycine Carbonate 6.90 mg Crosspovidone (Kollidon ® CL) 10.00 mgAspartame 0.30 mg Fresh-flavour 0.30 mg Magnesium Stearate 2.00 mg (b)Amorphine tablets (10 mg) Apomorphine hydrochloride 10.00 mg Mannitol(Peariltol ® DC 200) 130.40 mg Fumaric acid 20.00 mg Sodium GlycineCarbonate 6.90 mg Crospovidone (Kollidon ® CL) 10.00 mg Aspartame 0.30mg Aluminum lake (E110 20%) 0.10 mg Fresh-flavour 0.30 mg MagnesiumStearate 2.00 mg (c) Apomorphine tablets (20 mg) Apomorphinehydrochloride 20.00 mg Mannitol (Pearlitol ® DC 200) 119.50 mg Fumaricacid 20.00 mg Sodium Glycine Carbonate 6.90 mg Crospovidone (Kollidon ®CL) 20.00 mg Aspartame 0.30 mg Aluminum lake (E11 20%) 0.50 mgFresh-flavour 0.30 mg Magnesium Stearate 2.50 mg

EXAMPLE 19

[0105] The oral absorption profile of levodopa and carbidopa releasedfrom effervescent tablets of LDME/carbidopa monohydrate combinationprepared according to example 14 was compared to that oflevodopa/carbidopa monohydrate commercially available standard tablets(Sinemet®).

[0106] The study was carried out after single oral dose administrationof the two formulations in six healthy volunteers according to across-over design.

[0107] The results, reported in tables 7 and 8 show a more rapidabsorption and an active ingredients higher exposure during the firsthours after administration of the effervescent formulation in comparisonto the standard commercial formulation.

[0108] In the table Cp=plasma Concentration; Cmax=maximum plasmaConcentration; Tmax=Time to maximum concentration; AUC1h, AUC2h,AUCt=Area Under the Curve of plasma concentration vs time after 1 hour,2 hours and total, respectively. TABLE 7 Main pharmacokinetic parametersof Levodopa (geometric mean ± standard deviation) after oraladministration, of effervescent tablets of LDME/Carbidopa monohydratecombination of example 14 vs standard commercial tablets ofLevodopa/Carbidopa monohydrate combination (Sinemet ®) in six healthyvolounteers Levodopa pharmacokinetic Sinemet ® LDME/Carbidopa parameterstablets effervescent tablets Cp 15 min 1292 ± 321  2787 ± 1338 (ng/mL)Cp 30 min 965 ± 304 1705 ± 989  (ng/mL) Cp 45 min 1158 ± 703  1339 ±882  (ng/mL) Cp 1 h 999 ± 541 1023 ± 691  (ng/mL) Cmax 2218 ± 1289 3000± 1592 (ng/mL) Tmax 0.6 ± 0.3 0.3 ± 0.2 (h) AUC 1 h 986 ± 466 1683 ±1074 (ng · h/mL) AUC t 5473 ± 4678 5123 ± 4485 (ng · h/mL)

[0109] TABLE 8 Main pharmacokinetic parameters of Levodopa (geometricmean ± standard deviation) after oral administration, of effervescenttablets of LDME/Carbidopa monohydrate combination of example 14 vsstandard commercial tablets of Levodopa/Carbidopa monohydratecombination (Sinemet ®) in six healthy volounteers Levodopapharmacokinetic Sinemet ® LDME/Carbidopa parameters tablets effervescenttablets Cp 30 min 52 ± 31 46 ± 33 (ng/mL) Cp 45 min 52 ± 32 63 ± 46(ng/mL) Cp 1 h 59 ± 39 66 ± 45 (ng/mL) Cp 1.5 h 69 ± 47 72 ± 46 (ng/mL)Cp 2 h 49 ± 32 68 ± 42 (ng/mL) Cmax 75 ± 51 88 ± 65 ng/mL) Tmax 2.6 ±1.7 1.5 ± 0.8 (h) AUC 2 h 44 ± 12 105 ± 72  (ng · /mL) AUC t 230 ± 144255 ± 168 (ng · h/mL)

[0110] This application is a Continuation-in-Part of U.S. applicationSer. No. 09/463,224, filed Mar. 21, 2000. The full text of thatapplication is incorporated herein by reference.

What is claimed:
 1. A pharmaceutical composition in form of effervescentor fast-dissolving tablet comprising an active ingredient and aneffervescent couple, the couple comprising an acidic component and analkaline component, wherein the active ingredient is selected frompiroxicam-β-(CD), ambroxol hydrochloride, paracetamol, domperidone,nimesulide, ibuprofen, morniflumate and apomorphine, the acidiccomponent is selected from fumaric acid, maleic acid or their salts andthe alkaline component is sodium glycine carbonate.
 2. A pharmaceuticalcomposition according to claim 1, further comprising at least oneadditional excipient selected from the group consisting of ligands,lubricants, sweeteners, solubilizers, colorings, flavourings, diluents,disintegrants, wetting agents and mixtures thereof.
 3. A pharmaceuticalcomposition in form of effervescent or fast-dissolving tablet comprisingan active ingredient and an effervescent couple, the couple comprisingan acidic component and an alkaline component, wherein the activeingredient is selected from piroxicam-β-(CD), ambroxol hydrochloride,paracetamol, domperidone, nimesulide, ibuprofen, and morniflumate, theacidic component is selected from fumaric acid, maleic acid or theirsalts and the alkaline component is sodium glycine carbonate.
 4. Apharmaceutical composition according to claim 3, further comprising atleast one additional excipient selected from the group consisting ofligands, lubricants, sweeteners, solubilizers, colorings, flavourings,diluents, disintegrants, wetting agents and mixtures thereof.
 5. Apharmaceutical composition in form of effervescent or fast-dissolvingtablet comprising an active ingredient and an effervescent couple, thecouple comprising an acidic component and an alkaline component, whereinthe active ingredient is apomorphine, the acidic component is selectedfrom fumaric acid, maleic acid or their salts and the alkaline componentis sodium glycine carbonate.
 6. A pharmaceutical composition accordingto claim 5, further comprising at least one additional excipientselected from the group consisting of ligands, lubricants, sweeteners,solubilizers, colorings, flavourings, diluents, disintegrants, wettingagents and mixtures thereof.